CD8+T-cellWords
-- Mouse study suggests a risk of serious side effects with peptide
vaccines --
(To be published on ScienceNOW, "Science" magazine's website, on Thursday, January 19th)
T-cells – crucial players in the body's defense against viruses -- have good memories, but that could mean bad luck for vaccine recipients. According to a new study, vaccinating mice with peptides that mimic viruses to which the mice have already been exposed can be harmful. That’s because peptides trick the mouse’s T cells into making toxic antiviral compounds that – when present in large numbers – not only kill viruses, but also cause host symptome ranging from mild harm to death. These negative effects, say researchers at The Scripps Research Institute, are due to activation of too many T cells at one time. The study has implications for improving design of peptide vaccines for humans.
Peptide vaccines are new members in today’s arsenal of vaccination tools. The peptides – or proteins -- used in these vaccines bolster the immune system because they are identical to short sequences of virus proteins called epitopes. T cells learn to recognize epitopes, in different viruses, so that when next exposed to them, the T cells activate, attacking the epitopes and preventing infection in the host. Epitope injection in peptide vaccines also poses a risk, however; unlike DNA-based vaccines, for example, where proteins have to be processed before epitopes are in the proper form to activate T cells, peptide vaccines can activate T cells immediately. In naïve mice – those not previously exposed to a certain virus – immediate activation is necessary to prevent infection. But what happens if a recipient of a peptide vaccine already has a large number of T cells specific for the viral epitope being injected? That would make for quite a lot of T’s, both the old epitope-specific ones and the newly recruited ones, responding to peptide injection. And while tons of T cells tackling the trouble sounds like it would be beneficial, it’s not.
Researchers at Scripps Research Institute have determined how particular T cells, known as CD8+ cells, respond to peptide vaccines. At the Department of Neuropharmacology, J. Lindsay Whitton and colleagues, whose results will be published next month in The Journal of Clinical Investigation, infected mice with lymphocytic choriomeningitis virus, or LCMV. Eight days later, Whitton vaccinated these mice either with a peptide representing the LCMV epitope, or with saline alone. The saline-injected mice displayed no negative side effects, but the peptide-injected mice developed several shocklike symptoms, including hypothermia, and died within 24 hours of injection. (Whitton and his colleagues identified TNF – tumor necrosis factor – as the molecule responsible for the temperature drop and the lethal effects in these mice. The TNF, they discovered, was produced by the CD8+ T cells in response to the LCMV peptide.) Thus, peptide injection in a naive individual does not activate large numbers of T cells, since the T cells present have not yet seen the virus, nor had a chance to congregate in epitope-specific pools. However, this same peptide injection activats numerous T cells – thereby harming the host -- in an individual who has been previously exposed to the virus. Whitton was careful to explain that “this study is a cautionary flag for peptide vaccines, and not an indication to abandon ship.”
Matthias von Herrath, head of the Immune Regulation Lab at La Jolla’s Institute for Allergy and Immunology agrees, saying that peptide vaccines are useful, “as long as we ensure that they cannot cause synchronous activation of pre-existing T cells.”
Mark Larche, Ph. D. and Senior Research Fellow at the Imperial College of London’s Department of Clinical Immunology, also corroborates on the potential for peptide vaccines. He attributes their negative side effects to dosage issues. “The message of this study is that yes, you will have problems with the wrong -- too high -- dose of peptides, but that does not mean peptides will not be good vaccine components. Peptide vaccines offer the ultimate in specificity. It’s just that great attention must be paid to defining doses so as not to cause activation of huge numbers of T cells.”
Larche has done work similar to Whitton’s in asthma patients, administering synthetic peptides that elicit T cell responses. “We have spent a lot of time working out the dose relationships,” he explained, “and you can avoid negative side effects with peptide vaccines while still achieving immunological tolerance, by delivering low doses. The correct dose-finding studies in humans should make this effect less of an issue. Essentially, you want to induce an immune response with these vaccines, but you don't want to induce a response so great that the antiviral effects, like TNF, end up killing the subject. Everything in moderation...just like everything else in life.”
.MGW.
vaccines --
(To be published on ScienceNOW, "Science" magazine's website, on Thursday, January 19th)
T-cells – crucial players in the body's defense against viruses -- have good memories, but that could mean bad luck for vaccine recipients. According to a new study, vaccinating mice with peptides that mimic viruses to which the mice have already been exposed can be harmful. That’s because peptides trick the mouse’s T cells into making toxic antiviral compounds that – when present in large numbers – not only kill viruses, but also cause host symptome ranging from mild harm to death. These negative effects, say researchers at The Scripps Research Institute, are due to activation of too many T cells at one time. The study has implications for improving design of peptide vaccines for humans.
Peptide vaccines are new members in today’s arsenal of vaccination tools. The peptides – or proteins -- used in these vaccines bolster the immune system because they are identical to short sequences of virus proteins called epitopes. T cells learn to recognize epitopes, in different viruses, so that when next exposed to them, the T cells activate, attacking the epitopes and preventing infection in the host. Epitope injection in peptide vaccines also poses a risk, however; unlike DNA-based vaccines, for example, where proteins have to be processed before epitopes are in the proper form to activate T cells, peptide vaccines can activate T cells immediately. In naïve mice – those not previously exposed to a certain virus – immediate activation is necessary to prevent infection. But what happens if a recipient of a peptide vaccine already has a large number of T cells specific for the viral epitope being injected? That would make for quite a lot of T’s, both the old epitope-specific ones and the newly recruited ones, responding to peptide injection. And while tons of T cells tackling the trouble sounds like it would be beneficial, it’s not.
Researchers at Scripps Research Institute have determined how particular T cells, known as CD8+ cells, respond to peptide vaccines. At the Department of Neuropharmacology, J. Lindsay Whitton and colleagues, whose results will be published next month in The Journal of Clinical Investigation, infected mice with lymphocytic choriomeningitis virus, or LCMV. Eight days later, Whitton vaccinated these mice either with a peptide representing the LCMV epitope, or with saline alone. The saline-injected mice displayed no negative side effects, but the peptide-injected mice developed several shocklike symptoms, including hypothermia, and died within 24 hours of injection. (Whitton and his colleagues identified TNF – tumor necrosis factor – as the molecule responsible for the temperature drop and the lethal effects in these mice. The TNF, they discovered, was produced by the CD8+ T cells in response to the LCMV peptide.) Thus, peptide injection in a naive individual does not activate large numbers of T cells, since the T cells present have not yet seen the virus, nor had a chance to congregate in epitope-specific pools. However, this same peptide injection activats numerous T cells – thereby harming the host -- in an individual who has been previously exposed to the virus. Whitton was careful to explain that “this study is a cautionary flag for peptide vaccines, and not an indication to abandon ship.”
Matthias von Herrath, head of the Immune Regulation Lab at La Jolla’s Institute for Allergy and Immunology agrees, saying that peptide vaccines are useful, “as long as we ensure that they cannot cause synchronous activation of pre-existing T cells.”
Mark Larche, Ph. D. and Senior Research Fellow at the Imperial College of London’s Department of Clinical Immunology, also corroborates on the potential for peptide vaccines. He attributes their negative side effects to dosage issues. “The message of this study is that yes, you will have problems with the wrong -- too high -- dose of peptides, but that does not mean peptides will not be good vaccine components. Peptide vaccines offer the ultimate in specificity. It’s just that great attention must be paid to defining doses so as not to cause activation of huge numbers of T cells.”
Larche has done work similar to Whitton’s in asthma patients, administering synthetic peptides that elicit T cell responses. “We have spent a lot of time working out the dose relationships,” he explained, “and you can avoid negative side effects with peptide vaccines while still achieving immunological tolerance, by delivering low doses. The correct dose-finding studies in humans should make this effect less of an issue. Essentially, you want to induce an immune response with these vaccines, but you don't want to induce a response so great that the antiviral effects, like TNF, end up killing the subject. Everything in moderation...just like everything else in life.”
.MGW.
posted by Meagan G at
5:06 PM
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